Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of neurodegenerative diseases affecting a wide variety of mammals including sheep and goats (scrapie), cervid spp. (chronic wasting disease), and humans (Creutzfeldt-Jakob disease). A central event in TSE disease involves the conversion of the normal host cellular prion protein (PrPC) to a partially protease-resistant, aggregated, disease-associated isoform (PrPSc). TSE-induced pathology is usually associated with PrP-res deposition, but the mechanism of neurodegeneration is not understood. Like prion diseases, other neurodegenerative diseases involve the deposition of pathological protein aggregates including Alzheimers and Parkinsons disease. Collectively, these diseases are termed protein misfolding diseases because they are associated with the accumulation of misfolded host proteins. Critical processes for transmission of prions between and within hosts include neuroinvasion and intercellular spread of PrPSc. The glycosylphosphatidylinositol (GPI)-anchor of PrP may have an important role in modulating these processes. Our work in this project is focused on elucidating the role of GPI anchoring in modulating the aggregation and intercellular spread of aggregation-prone proteins. In 2009, we have: 1) further studied novel cell culture models and visualized the formation, fragmentation, and intercellular spread of aggregates of a GPI-anchored yeast prion protein in mammalian cells;and 2) characterized the ultrastructure of these aggregates by immunoelectron microscopy. This work has led to one manuscript currently under review.